Director, Research Program on Aging, Cognition and Alzheimer’s Disease
Associate Director, Centre for the Studies on the Prevention of Alzheimer’s disease
Douglas Mental Health University Institute

Alzheimer's Disease Genetics Research

Research Summary

ADGEN: Alzheimer's Disease Genetics Research Unit
Under the leadership of Dr. Judes Poirier, C.Q., ADGEN is a research unit dedicated to the understanding of the genetics and molecular neurobiology of dementing illnesses such as Alzheimer's disease (AD) and Vascular dementia (VD). It's research strategy is focused on the use of a broad class of drugs, which ADGEN refers to as "apolipoprotein E inducers", in the treatment and prevention of neurodegenerative diseases such as AD. There is an estimated 6 million persons suffering from Alzheimer's disease in North America ( > 36 million worldwide) and twice as many who are "at risk" of developing the disease in the next 15 years. ADGEN's research team believes that its patented technologies and research approaches represent major advancements in the fight against dementias. It is estimated that more than $200 billion dollars are spent every year on direct and indirect health care cost and lost working days in North America because of Alzheimer's disease. Our pioneering work on the role of genetic risk factors in disease etiology and therapy has allowed us to identify several genetic variants that affect either, the age of onset, the rate of progression or the quality of the drug response to memory enhancer medications. The most common genetic defect identified so far involves a critical transporter of brain cholesterol called apolipoprotein E (apoE) and a neurotransmitter degrading enzyme called butyrylcholinesterase (BuChE). Using unique genetic signatures, we have characterized the biological functions of key modulators of lipid physiology in the brain and screened a large number of chemical entities capable of restoring impaired lipid homeostasis in the brain of affected AD subjects. This pioneering work led to the successful identification of several potential pharmacological targets, including a few potent apoE inducers. In recent year, we have chosen to focus on a particular compound which was used several years ago to lower blood cholesterol in humans. This led to the development of an extensive pre- clinical research program in brain rodent and human cell cultures, mice and rat models, and more importantly, to a small proof-of-principle clinical trial in humans suffering from mild-to- moderate AD. Final results clearly indicate that it is possible to modify the brain's lipid chemistry and to enhance lipid mobilisation, to slow down disease progression and to reduce the burden of toxic brain byproducts such as phospho-Tau, a protein commonly associated with AD pathology. Recently, Pfizer and Eli Lilly have expressed interested in the lipid transporter-based therapy field by launching new, but small, initiatives to tackle this emerging field of research in AD. Although there are a few medications designed to improve memory deficits in AD subjects, none of these treatments halt or slow down the progression, or delay onset of the disease in a significant manner. At best, the clinical benefits last 6 to 18 months, and only in a modest subset of patients. Furthermore, recent attempts by small and large pharmaceutical corporations to interfere with one of Alzheimer’s pathological hallmark called amyloid by means of vaccines (Elan, Wyett-Ayerst), inhibitors of synthesis (Astrazeneca, SKB, GSK and Ely Lilly) and disaggregating agents (Parke-Davis, Neurochem) have failed so far to meet FDA requirements.

Key Publications

Brain Reinnervation and Apolipoprotein E Neurobiology
The initial phase of our research program has been to identify key mRNAs involved in synaptic remodelling in the injured adult rodent brain. In an article published in Proc. Natl. Acad. Sci. 87:303, we documented the fact that a limited numbers of mRNAs of moderate prevalence exhibit significant induction during the active phase of reinnervation in the experimentally deafferented rat hippocampus (a partial model of Alzheimer's disease pathology). The most important transcript identified during follow-up cDNA screenings turned out to be a protein known as apolipoprotein E (apoE), a well-characterized cholesterol transporter produced locally in the brain.

Apolipoprotein E4 and the Pathophysiology of Alzheimer’s disease
In a series of follow-up studies in neurodegenerative diseases, we published a breakthrough report in the Lancet 342: 697 where we reported that sporadic cases with Alzheimer's disease (AD) exhibit an abnormally high incidence of a normally rare apoE allele referred to as the apoE4. Follow-up publications by our team demonstrated a potent apoE4-gene dose effect on : a) age of onset, b) rate of progression, c) risk of developing the disease and more importantly, d) on the cholinergic status and integrity in the brain of sporadic Alzheimer’s disease subjects: Proc. Natl. Acad. Sci. 92: 12260, Lancet 347: 1091, J.A.M.A. 278: 1349, Proc. Natl. Acad. Sci. 98: 10966.

Apolipoprotein E influences the Beta-Amyloid Neurotoxicity and Metabolism
In more recent years, we uncovered the biological connection linking the so-called beta amyloid cascade hypothesis of AD and apolipoprotein E metabolism in the pathophysiology of Alzheimer’s disease. Using various techniques, models and approaches, we documented the apoE/beta amyloid relationship in vitro and in vivo. The studies were published in Nature 387: 500, J. Neurochem. 66:2410, J. Neurochem. 70:1466, Brain Research Reviews 27: 199 Apolipoprotein E4: A Pharmacogenomic Marker of Drug Efficacy in Alzheimer’s disease: Our modest but significant contribution to the emerging field of the pharmacogenomics prompted several pharmaceutical corporations (Eli Lilly, Bayer, Parke Davis, Novartis and Smith Kline Beecham) to re-evaluate their clinical drug trial designs to include an apoE genotype arm. We and others have documented on multiple occasions the fact that the efficacy of several memory enhancers (especially cholinomimetics) are highly dependent upon the individual’s apoE or BuChE K genotypes Proc. Natl. Acad. Sci. 92: 12260, Neurology 50: 669, Curr. Pharmacogen. 8: 63 this key contribution to canadian translation research effort was recognized by the Galien 1996 Prize and Genesis Awards 2010 Cholesterol Metabolism as Therapeutic Target for the Treatment of Alzheimer’s Disease: As early as 1993, we proposed that the reduction in apoE concentrations reported in the blood and brain of apoE4 allele carriers could be alleviated by drugs that specifically promote apoE synthesis and secretion in the CNS. Building on the approach, we identified three different agents (out of several hundreds) with strong apoE inducing capacity: estrogen, indomethacin and probucol (Eur. J. Neurosci. 18: 1, Neuroscience 121: 99, Alz. Dem. 4: 591, Curr Alz Res 5:33) . Independently of this work, these three compounds had been shown to reduce the risk of developing AD in several epidemiological studies ran in the US, Europe and Asia. As a consequence, we choose to focus on the drug Probucol, a potent cholesterol-lowering agent for efficacy and safety reasons. In a small proof-of-principal study performed in Montreal (Adv. Behav. Biol. 51: 39, Trends Mol. Medicine 9:94, Neurobiol. Aging 2014), we discovered that a 6-month treatment with Probucol in mild-to-moderate AD stopped disease progression in the majority of the 12 patients enrolled in the study and “improved” the activities of daily living for the entire group.

Bio

Dr. Poirier received his undergraduate training at the “Université de Montréal” in biochemistry. Shortly after, he joined Dr. André Barbeau’s group at the Clinical Research Institute of Montreal where he completed his Ph.D. on the neurobiology of Parkinson’s disease and the neurotoxicity of MPTP and Aluminum. He was then invited to join the Alzheimer’s Disease Research Consortium of Southern California in Los Angeles as research associate. It is in California that he discovered the important role of apolipoprotein E, a key cholesterol trans-porter that acts as a powerful modulator of brain repair and, serves as a key player in Alzheimer’s disease pathophysiology. McGill University and the Douglas Institute recruited him back in the spring of 89 to establish a research program specialised in neurodegenerative diseases with a strong focus on Alzheimer’s disease genetics.